There is presently a severe and growing shortage of available human organ donors. Considerable interest has focused recently on the use of pigs as a potential source of transplant organs. Once hyperacute rejection was prevented, it became apparent that fulminant acute rejection is the major obstacle blocking the widespread use of pig organ xenografts. The severe immune suppression required to prevent this rejection would lead to an unacceptably high mortality rate. We have proposed a new approach to xenotransplantation, called "surrogate tolerogenesis" where tolerance is induced outside of the organ recipient, within the animal organ donor. This should greatly decrease the need for immune suppression. Initial phase I results using sheep as organ recipients, in fact, supported this proposition, where prolonged graft survival was achieved with only minimal suppression. Using large animal xenotransplant models, the proposed studies will further develop and evaluate surrogate tolerogenesis, in preparation for initial clinical studies of kidney transplants. The specific aims are to: 1. Evaluate potential improvements of surrogate tolerogenesis. 2. Assess the long term potential and complications of surrogate tolerogenesis. 3. Determine effectiveness in a discordant xenotransplant model. 4. Determine the cell populations essential for the transfer of tolerance back to the recipient. PROPOSED COMMERCIAL APPLICATION: As defined by the severe shortage of human organ donors, the demand for pig xenografts is expected to be great. Kidney grafts are cost effective compared with hemodialysis, but the savings is limited by the shortage of human kidneys. This technology could save considerable funds by providing grafts to those without donors and by minimizing complications from immune suppression. The technology would also apply to other organ grafts, such as heart, liver, etc.